New Insights into PAD2 Enzyme's Role in Pancreatic Cancer Progression

Recent research conducted by scientists at the Institute of Science Tokyo has unveiled the significant role of the enzyme peptidyl-arginine deiminase 2 (PAD2) in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Using advanced genetic manipulation techniques on pancreatic cancer cell lines and mouse models, researchers demonstrated that PAD2 facilitates tumor growth by promoting histone citrullination — a chemical modification of histone proteins that enhances gene expression. Their studies showed that increased PAD2 activity correlates with elevated expression of the PRUNE1 gene, which is associated with heightened cell proliferation and alteration of the tumor microenvironment.

The team’s immunohistochemistry analysis of patient tissue samples revealed that histone citrullination is more prevalent in PDAC tissues compared to normal pancreatic tissue and is linked to poorer overall survival rates. Manipulating PAD2 levels in cancer cells confirmed that overexpression of PAD2 accelerated cell proliferation, while its knockdown reduced tumor cell growth. In vivo experiments further substantiated these findings, as tumors derived from PAD2-overexpressing cells exhibited increased growth and immune cell infiltration, notably an influx of tumor-promoting M2 macrophages.

Crucially, treatment with PAD inhibitors, including Cl-amidine (a general PAD inhibitor) and AFM-30a (a PAD2-specific inhibitor), lowered PRUNE1 expression and significantly hindered tumor development in mouse models. These promising results suggest that targeting PAD2 enzymatic activity could serve as a potential strategy for epigenetic therapy in pancreatic cancer. Overall, this study highlights PAD2 as a key driver of PDAC progression and offers new avenues for therapeutic intervention.

Source: https://medicalxpress.com/news/2025-08-pad2-enzyme-key-driver-pancreatic.html